It has long been disputed whether sex hormones play a role in immune regulation and specifically in systemic lupus erythematosus. We have demonstrated that estradiol can alter the threshold for negative selection of naive autoreactive B cells. Estradiol, at 75 l00pg/ml will break tolerance for anti-DNA marginal zone B cells in BALB/c mice, but not in C57Bl/6 mice. We have further demonstrated that the survival of autoreactive B cell is distinct from activation of these cells. We now propose to understand what genes and pathways are involved in estrogen-mediated B cell survival and B cell activation. We will ask how estrogen leads to an increase specifically cells in the marginal zone B cell subset. Finally, we will investigate the differences in B cell responsiveness to estrogen in BALB/c and C57Bl/6 mice to understand what underlies an estrogen mediated breakdown in humoral self- tolerance.